Process for preparing lobelia alkaloids, their derivatives and allied compounds



Patented Feb. 6, 1934 I UNHTEE STATEQ PATENT GFFICE PEOiJESS FOR PREPARENG LOBELIA ALKA- LOIDS, THEIR DERIVATIVES AND ALLEED CQMPQUNDS of Germany N Drawing.

Application June 24, 1929, Serial No. 373,467, and in Germany June 29, 1928 14 Claims.

Hitherto the lobelia alkaloids, which are therapeutically valuable as specific stimulants of the respiratory centre, have been obtained by extraction from lobelia plants. During this extraction, however, considerable quantities of inactive or only slightly active and, consequently, hitherto unusable secondary alkaloids have been simultaneously produced.

It has now been found that the inactive or only slightly active lobelanidine, which occurs in considerable quantities in the lobeline mother liquors, may be converted by oxidation into the valuable alkaloids, lobeline and lobelanine. Further experiments based on the above facts have now led to the susprising result that the lobelia alkaloids are to be considered as derivatives of piperidine. This is surprising inasmuch as the supposition hitherto has been that the two oxygen atoms in lobelanine were present in the form of inner ether groups (of. Annalen (444) 41 (1925)).

It has now been established that lobelanidine, lobelanine and lobeline have the following constitutional formulae? (1 Lobelanidine 011011 6 OaHs Lobelanine (3) Lobeline i l oH2\ on, 011011 5 0 o It is accordingly possible to obtain lobeline by oxidation of the di-alcohol lobelanidine, for example the natural lobelanidine occurring amongst the secondary alkaloids of lobeline and, by oxidation of lobelanidine or lobeline, to obtain the corresponding di-ketone lobelanine. Conversely, lobelanine and lobeline may be converted by hydrogenation into lobelanidine.

Starting from this newly recognized fact, it was further found that, by oxidizing compounds, which correspond to the lobelanidine type and are derived from piperidine or from pyridine, it is in general possible to obtain compounds, which,

owing to their close connection to the lobelia alkaloids, have a therapeutic interest.

Compounds substituted on both sides, for example of the following types:

may, for example, be subjected to oxidation and in this way compounds closely allied to lobeline and lobelanine be directly obtained. R, R1 and R2 may represent, for example, alkyl, arakyl, or aryl residues, if desired also residues of a heterocyclic nature, which may be of the same or of different kinds. B may also represent hydrogen. The piperidine or pyridine nucleus may also contain other substituents, such as alkyl residues, hydroxyl, halogen and the like.

Piperidine derivatives or pyridine derivatives, which contain only one alcoholic side chain, may also be employed as starting materials, for example, compounds of the type:

CHOH OOH R1 B1 In this case also substituents, such as alkyl residues, hydroxyl, halogen, etc. may be present in the piperidine or pyridine nucleus.

Further pyridine or piperidine derivatives having more than one nucleus, for example unhydrogenated or hydrogenated quinoline compounds, may also be employed, for example those which are partially hydrogenated, for example tetrahydrogenated in the nucleus or in the side chains, if desired in the radical R1, or which are entirely hydrogenated (perhydrogenated) with removal of all double bonds, for example compounds of the following type:

The oxidation processes maybe effected with the aid of the usual oxidizing agents, for example permanganate or pyrolusite in dilute sulphuric acid solution or chromic acid in acetic acid solution, or may be effected by means of electrolysis. In all cases, the corresponding dior mono-keto compounds may be obtained by oxidation. According to thenature and quantity of the oxidizing agent and the method of employing the same, the process may be infiuenced so as to form mono-ketones or di-ketones, for example in such a way that lobeline is obtained as themain product together 'with more or less lobelanine. If it is, for example, desired exclusively to prepare lobelanine, the oxidizing agent is, for example, employed in the quantity theoretically required for carrying out the process or in excess thereof.

If, on the other hand, lobeline is the desired product, it is advisable, for example when cmpl'oying pyrolusite and sulphuric acid, to employ a correspondingly smaller quantity of the oxidizing agent and to perform the reaction cautiously.

When two side chains are present, each of which contains a secondary alcoholic group, mono-ketones may be obtained which still contain one alcoholic hydroxyl group, for example compounds of the lobeline type, by carefully regulating the oxidation process by employing, for example, pyrolusite and sulphuric acid.

According to one modification of the invention the di-ketone, for example lobelanine, obtained as a by-product in the production of lobeline or other compounds of the lobeline type, may be reconverted by hydrogenation, for example catalytic hydrogenation, into lobelanidine and the latter converted by renewed oxidation into the desired product, for example lobeline.

The following examples serve to illustrate how the invention may be carried into effect:

1. 10 gills. of lobelanidine are dissolved in 560 cc. of 5% sulphuric acid and treated in the cold with concentrated nitric acid. A further small quantity of lobelanine-nitrate is obtained which "lay be reconverted by hydrogenation into lobelanidine and, together with the unchanged lobelanidine, may be employed for a new batch.

2. It is preferable to use freshly precipitated pyrolusite rather than permanganate in the partial oxidation of lobelanidine to lobeline.

5 gms. of lobelanidine are dissolved with stirring in 500 ccs. of about 5% sulphuric acid and treated with 1.4 gins. (calculated quantity 1.28 gms.) of freshly precipitated pyrolusite. After about 4 to 5 hours the vigorously stirred solution becomes water clear. The solution is made alkaline with caustic soda, the base taken up in chloroform, the dried chloroform solution evaporated and the residueextracted by boiling with ether' 1.5 gms. of lobelanidine remain undissolved by the ether in the form of powder. The ethereal solution is evaporated and yields 1.8 gms. of crude lobelidine (d,l-lobeline) of melting point 104-110 C. (about 80% of pure lobelidine may be recovered therefrom). The residual base amounts to 1.5 gms. and is worked up by way of the hydrochloride to lobelanine. In this way none of the material employed is lost.

3.8 gms. of nor-lobelanidine (which is like lobelanidine excepting that the methyl group attached to the nitrogen atom is substituted by a hyrogen atom) are brought into reaction, in the manner described in Example 2, with 0.8 gm. of freshly "precipitated pyrolusitef The bases taken up in the ether yield, after neutralizing with alcoholic hydrochloric acid and on fractional addition of ether, first 1.2 gms. of the hydrochloride of the starting material, then 0.8 gm. of nor-lobelidine hydrochloride of melting point 192-197 C. The residue consists of the hydrochloride of nor-lobelanine.

The nor-lobelidine hydrochloride resembles the lobelidine salt. It is readily soluble in water and crystallizes from alcohol-ether in clusters, which, however, are not compact but are radially distributed. Melting point 291-202" C.

4:. 5 gms. of perhydio-nor-lobelanidine hydrochloride (a compound much like nor-lobelanidine but having double bonds in the benzene groups of the side chains which are hydrogenated) of melting point 260 C. are dissolved in 500 ccs. of glacial acetic acid and treated in the warm with a concentrated aqueous solution of 5 gms. of chromic acid. After about 1 hour the yellow tint is changed to green, when the excess of acetic acid is distilled off in vacuo. The residue is dissolved in water, the solution made alkaline and extracted with ether' The ethereal solution is treated with the theoretically required quantity of alcoholic hydrochloric acid. The'salt which is first precipitated as an oil, crystallizes on rubbing with a glass rod. Yield 4 to 5 gms. of perhydro-norilobelanine. Melting point of the salt crystallized from acetone, 250 C.

acids, such as tartaric acid, or their salts.

melting point 130-13l 'plants, to be converted 5. '5 gms. of nor-lobelanidine hydrochloride are subjected to oxidation in a manner similar to that described in Example 4. 4.6 gms. of norlobelanine of melting point 120 C. are obtained. The hydrochloride melts at 201 C. (The melting point of the starting material was 244 C.).

6. 11 gms. of (3-hydroxy-B phenyl-ethyl-Z-pyridine (melting point 107 C.) are dissolved in 30 cos. of glacial acetic acid and treated with a mixture of '7 gms. of potassium bichromate, 19 cos. of concentrated sulphuric acid and 35 cos. of water. The solution is heated for 1 hour at 60-70" C. After cooling, the solution is made alkaline and extracted with ether. The ethereal residue, amounting to 6 gins, crystallizes on rubbing with a glass rod. The resulting phenacyl pyridine, having the phenacyl grouping CcH5-COCH2-,

and corresponding to the starting material melts at 57 C. after re-crystallization from methyl alcohol. (The melting point of the oxime is 120 (3.).

It was finally also found that compounds, which contain one or more asymmetric carbon atoms, such as compounds like d,1-lobeline (lobelidine), as well as derivatives of the same, such as nor-lobelidine (a compound analogous to lobelidine excepting that the methyl group attached to the nitrogen atom is replaced by a hydrogen atom) or the corresponding perhydro compounds, may be resolved into their optically active components. This may be eirected, for example, with the aid of suitable optically active Salts of d,1-lobeline may, for example, be treated with neutral tartrates, when a mixture of tartrates of l-lobeline crystallizes out, the composition of which varies according to the working conditions. Pure l-lobeline is obtained by repeated crystallization of these salts and precipitation of the bases, whilst the d-lobeline may be recovered from the mother liquors.

7. 10 gms. of d,l-lobeline hydrochloride are dissolved in 20 cos. of water and treated with the calculated quantity of 6.2 gins. of sodium tartrate dissolved in 10 cos. of water. A light oil is precipitated which soon sets, especially when seeded with the tartrate of l-lobeline. On re-crystallization, long needles melting at C. and consisting of the tartrate of l-lobeline and polyhedral clusters of crystals of melting point 180 C. which probably contain l-lobeline-sodium tartrate, are obtained side by side. A base of 0., which consists of l-lobeline, is obtained from both salts.

From the mother liquors the considerably more readily soluble tartrate of the d-lobeline may be recovered.

The present process enables lobelanidine, such as may be recovered from the mother liquors in the process of preparing lobeline from lobelia into therapeutically valuable products, such as lobelanine and lobeline and also lobelanine to be converted into lobeline by way of lobelanidine. It therefore represents a valuable advance in the synthesis of d,1-lobeline and its optically active components. The invention at the same time enables numerous new derivatives of the lobelia alkaloids and allied compounds to be prepared synthetically.

What I claim is:

1. A process for preparing compounds of the type of lobelia alkaloids, which consists in treating a compound, which contains in a ring consisting of five carbon atoms and one nitrogen atom, a ,8 hydroxy-c-phenyl-ethyl group in each of the a and 11' positions to the nitrogen atom, with an oxidizing agent commonly used for the oxidation of an alcohol to the corresponding ketone, until one of the hydroxyl groups is converted into a carbonyl group.

2. A process for preparing compounds of the type of lobelia alkaloids, which consists in treating a compound, which contains in a ring consisting of five carbon atoms and one nitrogen atom, an alkyl group at the nitrogen atom and ,c-hydroxy-c-phenyl-ethyl group in each of the a and or positions to the nitrogen atom, with an oxidizing agent commonly used for the oxidation of an alcohol to the corresponding ketone, until one of the hydroxyl groups is converted into a carbonyl group.

3. A process for preparing compounds of the type of lobelia alkaloids, which consists in treating a compound, which contains in a ring consisting of five carbon atoms and one nitrogen atom, an alkyl group at the nitrogen atom and a p-hydroxy-phenyl-ethyl group in each of the or and oz positions to the nitrogen atom with an oxidizing agent commonly used for the oxidation of an alcohol to the corresponding ketone, in a quantity substantially sufficient to convert both hydroxyl groups into carbonyl groups.

4. A process for preparing compounds of the type of the lobelia alkaloids, which consists in treating a compound, which, in a ring system consisting of five carbon atoms and one nitrogen atom, contains in at least one of the at positions to the nitrogen atom a c-hydroxy-p-phenyl-ethyl group with an oxidizing agent commonly used for the oxidation of an alcohol to the corresponding ketone, until at least one hydroxyl group is converted into a carbonyl group.

5. A process for preparing compounds of the type of the lobelia alkaloids, which consists in treating a compound, which, in a ring consisting of five carbon atoms and one nitrogen atom, contains in each of the 0c and at positions to the nitrogen atom a ,B-hydroxy-fl-phenyl-ethyl group with an oxidizing agent commonly used for the oxidation of an alcohol to the corresponding ketone until each of the hydroxyl groups is converted into a carbonyl group.

6. A process for preparing compounds of the type of lobelia alkaloids, which consists in treating a compound, which contains in a pyridine nucleus in at least one of the 0: positions to the nitrogen atom a ,6-hydroxy-fi-phenyl-ethyl group, with an oxidizing agent commonly used for the oxidation of an alcohol to the corresponding ketone, until at least one hydroxyl group is converted into a carbonyl group.

7. A process for preparing compounds of the type of lobelia alkaloids, which consists in treating a compound, which contains in a piperidine nucleus, in at least one of the 0: positions to the nitrogen atom, a B-hydroxy-fl--phenyl-ethyl group with an oxidizing agent commonly used for the oxidation of an alcohol to the corresponding ketone until at least one hydroxyl group is converted into a carbonyl group.

8. A process for preparing compounds of the type of lobelia alkaloids, which consists in treating a compound, which contains in an N-alkylated piperidine nucleus in at least one of the or positions to the nitrogen atom a fi-hydroxy-pphenyl-ethyl group with an oxidizing agent commonly used for the oxidation of an alcohol to the corresponding ketone until at least one hydroxyl group is converted into a carbonyl group.

9. A process which consists in treating a, ondi-(fi-hydroxy-p-phenyl-ethyl) piperidine (norlobelanidine) with an oxidizing agent commonly used for the oxidation of an alcohol to the corresponding ketone in an amount substantially suificient to convert only one of the hydroxyl groups into a carbonyl group.

10. A process which consists in treating 0:, ozdi-(fi-hydroxy-fl-phenyl-ethyl) piperidine (norlobelanidine) with an oxidizing agent commonly used for the oxidation of an alcohol to the corresponding ketone in an amount substantially sufficient to convert both hydroxyl groups into carbonyl groups.

11. A process which consists'in treating N- methyl-u, a-di(fi-hydroXy-[i-phenyl-ethyl) piperidine (lobelanidine) with an oxidizing agent commonly used for the oxidation of an alcohol to the corresponding ketone in an amount substantially sufficient to convert only one of the hydroxyl groups into a carbonyl group.

12. A process which consists in treating N- methylm, adi(B-hydroxy-B-phenyl-ethyl) piperidine (lobelanidine) with an oxidizing agent commonly used for the oxidation of an alcohol to the corresponding ketone in an amount substantially sufficient to convert both hydroxyl groups into carbonyl groups.

13. As a new compound: the hydrochloride of wphenacyl -a-(,8-hydroXy-fi-phenyl ethyl) -piperidine (nor-lobelidine) 14. A process which consists in treating a, ondi-(,8-hydroxy-,8-pheny1-ethyl) piperidine (norlo'oelanidine) with an oxidizing agent commonly used for the oxidation of an alcohol to the cor responding ketone, in an amount substantially sufiicient to convert only one of the hydroxyl groups into a carbonyl group, and then treating the resulting base with hydrochloric acid to form the hydrochloride salt (nor-lobelidine hydrochloride).

HEINRICH WIELAND. 

